Proteolytic Release of the p75^NTR Intracellular Domain by ADAM10 Promotes Metastasis and Resistance to Anoikis.

Abstract

Resistance to anoikis allows cancer cells to survive during systemic circulation; however, the mechanism underlying anoikis resistance remains unclear. Here we show that A disintegrin and metalloprotease 10 (ADAM10)-mediated cleavage of p75 neurotrophin receptor (p75^NTR) and subsequent generation of the p75^NTR intracellular domain (ICD) endow cancer cells with resistance to anoikis. p75^NTR ICD promoted expression of TNF receptor-associated factor 6 (TRAF6), a critical intermediary in p75^NTR ICD-mediated signal transduction, at the translational level. Cell detachment-induced activation of EGFR triggered autoubiquitination of TRAF6 by facilitating its dimerization, subsequently activated NFκB, and eventually led to anoikis resistance. ADAM10 and p75^NTR ICD also promoted tumor metastasis formation <i>in vivo</i> Together, our findings uncover a previously unknown function for the ADAM10-p75^NTR ICD-TRAF6-NFκB axis in preventing anoikis and suggest ADAM10 and p75^NTR ICD as potential cancer therapeutic targets.<b>Significance:</b> These findings identify the ADAM10-p75^NTR ICD-TRAF6-NFκB signaling axis as a potential candidate for cancer therapy. <i>Cancer Res; 78(9); 2262-76. ©2018 AACR</i>.